Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality?

Abstract

Oncology has entered in the era of personalized medicine with its advantages such as limited invasiveness during sample collection, robustness, precision and speed. This new era has led to novel practices of tissue sampling (e.g. needle biopsy) and the main goal of diagnostic medicine is now to detect crucial events in "infinitely" small samples. The key question is now to determine if the rare cell events isolated and characterized from these samples are reliably reflecting the initial and/or metastatic disease and particularly the heterogeneity of the tumor. The present review will give a short overview of the most recent methods developed for the isolation and characterization of rare cell events in clinical practice with a specific focus on circulating tumor cells. We will discuss the biological value to study these cells at the single cell level and how these rare cell events can reflect tumor heterogeneity. The potential biomedical applications (disease modeling, drug screening, therapeutic decision, monitoring, etc.) will be critically discussed in light of precision medicine.

Tracking cancer progression: from circulating tumor cells to metastasis

“…Single-cell analyses have revealed that CTCs often comprise a heterogeneous population of cells. Logically, this heterogeneity may reflect the extent of intratumor heterogeneity (ITH) [65][66][67][68][69][70] and may have important implications for prognosis and resistance to therapy. Indeed, a recent study of archived samples from patients with metastatic breast cancer found 85% concordance between CTCs and metastatic sites in terms of mutations and copy-number profile [71].…”

“…An additional study of metastatic breast cancer reported 85% concordance in single-nucleotide variant (SNV) mutations and copy-number alterations (CNAs) between paired CTCs and metastases [71]. However, as mentioned earlier, CTC profiling may not always recapitulate the heterogeneity of the entire tumor or metastatic lesion because of the low number of CTCs isolated from blood and the lack of statistical power to cover all tumor regions uniformly [67,71].…”

“…Challenges remain for the application of CTC-based technologies in the clinical setting, for instance, as a result of the low frequency of these cells in circulation. Whether or not a small tissue biopsy is representative of the whole tumor heterogeneity is a matter of debate, and this question prominently extends to the liquid biopsy field [67,71]. Although standard biopsy approaches hit a limited number of tumor regions that may or may not be relevant for disease progression (i.e., it is unclear whether they contain the most aggressive tumor subclones), CTCs are cells that have already undergone multiple selection processes and can be considered metastatic precursors.…”

The Heterogeneity of Osteosarcoma: The Role Played by Cancer Stem Cells

“…In addition, the clonal evolution of cancers is tightly controlled by the selective pressure of the local microenvironment (e.g. immune infiltrate, hypoxia), and can be oriented under drug pressure toward resistant or tolerant cancer cells (20,21). Regardless of what the first oncogenic event is, a permissive local micro-environment is obligatory for protecting cancer-initiating cells against immune cells and fuelling these cells with adequate nutrients (22).…”

Emerging Role of Circulating Tumor Cells in Gastric Cancer

“…This indicates that CD44 (+) /CD45 (−) CTCs functionally resemble or potentially are CSCs. Therefore, CTCs can mimic the genetic features of tumors at a given time and represent the current state of disease [86]. CTCs cultured in vitro can be used for drug sensitivity screening, a promising approach toward precision medicines.…”